This invention is generally directed to neuroprotective agents, pharmaceutical compositions containing the same, as well as to methods related to the use of such neuroprotective agents.
Neurotrophic factors are a group of proteinaceous compounds that participate in differentiation induction of neurons to maintain the existence and survival of cells, of which nerve growth factors (NGFs) are a representative class. NGFs are involved in the differentiation, existence, maintenance and/or repair of neurons in both the central and peripheral nervous systems of animals and represent a series of proteins having molecular weights of approximately 50,000 daltons.
Damage to nerves caused by either aging or internal/external factors often develop paphological symptoms. In the central nervous system, such damage is found to cause, for example, Alzheimer""s disease, dementia induced by cerebro-vascular disorders, disturbance of consciousness due to cerebral contusion, and tremor or muscle rigidity associated with Parkinson""s disease. Similarly, damage to the peripheral nervous system is associated with a number of conditions, such as amyotropic lateral sclerosis, spinal muscle atrophy, motor function disturbances due to neuron damage, neuropathy induced by diabetes mellitus, uremia, vitamin B1 or B12 deficiency, chronic liver disease, sarcoidosis, amyloidosis, hypothyrea, cancer, angiopathy, Sjxc3x6gren symptoms, immunopathy accompanied by infections, hereditary disease, physical compression, certain types of drugs (e.g., carcinostatic, tuberculostatic and/or anti-epileptic agents), or upon exposure to, for example, arsenic, thallium or carbon disulfide.
Since neurons may suffer damage from numerous events, indentification of a neurotropic factor which can regenerate and/or repair of damaged neurons is highly desirably. To this end, a recent attempt has involved the clinical application of NGF to conditions such as Alzheimer""s disease, neural damage or spinal injury. For example, when NGF is present, PC 12 cells terminate cell proliferation and differentiate into neuron-like cells with neurites. This has allowed screening for active substances which have NGF-like neuron differentiation/promoting activity. Substances identified in this manner include antibiotic staurosporin and certain cystacycline compounds. Unfortunately, both of these substances have drawbacks with respect to toxicity and kinetics.
More recently, compounds with neuron differentiation promoting activity have been reported in published PCT WO 99/05091 (Nippon Kayaku Co. Ltd.). Such compounds of this published PCT encompass a wide range of structures, including compounds of the following formulas (1A) through (1F): 
While significant advances have been made in this field, there is still a need in the art for novel neuroprotective agents, particularly low molecular weight compounds, as well as related compositions and methods of use. The present invention fulfills these needs and provides further related advantages.
In brief, the present invention is directed to compounds having activity as neuroprotective agents (also referred to herein as simply xe2x80x9ccompoundsxe2x80x9d), as well as to compositions and methods related thereto. As used herein, the term xe2x80x9cneuroprotective agentxe2x80x9d means a compound that prevents neuron cell death.
The compounds of the present invention have the following structure (I): 
wherein R1, R2, R3, R4 and R5 are as defined below, including stereoisomers and pharmaceutically acceptable salts thereof.
The present invention is also directed to methods for treating a variety of conditions by administering an effective amount of a neuroprotective agent of this invention to an animal or subject in need thereof (referred to herein as a xe2x80x9cpatientxe2x80x9d), typically a warm-blooded animal (including a human). Prior to administration, the compounds of this invention are preferably formulated as a pharmaceutical composition which contains an effective dosage amount of one or more neuroprotective agents in combination with one (or more) pharmaceutically acceptable carrier(s).
Conditions that may be treated by the compounds of this invention, or a pharmaceutical composition containing the same, include any condition which may benefit from administration of neuroprotective agents generally, and are particularly useful for the prevention and/or treatment of various conditions including (but not limited to) increased intracraniel pressure and cerebral herniation, cerebral edema, hydrocephalus, meningintis, encephalitis, ischemic encephalopathy, cerebral infarction, intracranial hemorrhage, epidermal hematoma, subdural hematoma, parenchymal injuries, Alzheimer""s deasease, Huntington""s disease, Parkinsonism, amytrophic lateral sclerosis, multiple sclerosis, hepatic encephalopathy, leukodystrophy, acute idiopathic neuropathy, neurilemmoma, and/or neurofibroma.
These and other aspects of this invention will be apparent upon reference to the following detailed description. To that end, certain patent and other documents are cited herein to more specifically set forth various aspects of this invention. Each of these documents are hereby incorporated by reference in their entirety.